Application of bifidobacterium animalis in improvement of tumor immunotherapy response

Abstract

The present disclosure relates to use of a probiotic composition in the manufacture of a drug for tumor treatment, the probiotic including Bifidobacterium animalis subsp. lactis. The drug further includes one or more tumor treatment drugs, such as an immune signaling pathway regulator PD-1/PDL-1. The drug is used for tumor immunotherapy.

1 . A method of treating a tumor, comprising administering a probiotic to a subject in need, wherein the probiotic comprises  Bifidobacterium animalis  subsp.  lactis.    
     
     
         2 . The method according to  claim 1 , wherein the probiotic comprises  Bifidobacterium animalis  subsp.  lactis  NexStrain 02 (Accession Number: CGMCC No. 20455). 
     
     
         3 . The method according to  claim 1 , wherein the probiotic comprises a bacterium with an evolutionary distance of less than 0.005 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;
 preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.001 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;   preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.0005 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;   preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.00005 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;   preferably, the probiotic comprises a bacterium with an evolutionary distance of 0 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;   maximal unique match (MRUM) between two genomes is calculated from the evolutionary distance by using a suffix tree algorithm of parsnp software, MUMi is calculated by using MRUM, and a value of the MUMi is a distance between the two genomes; and a MUMi calculation method is:   
       
         
           
             
               
                 MUMi 
                 = 
                 
                   1 
                   - 
                   
                     
                       L 
                       mum 
                     
                     / 
                     
                       L 
                       av 
                     
                   
                 
               
               , 
             
           
         
         wherein the L mum  refers to a base number of all MUMs, and L av  refers to a mean of the base numbers of the two genomes. 
       
     
     
         4 . The method according to  claim 1 , further comprises an application of one or more other tumor therapeutic drugs; preferably, the tumor therapeutic drug is an immune signaling pathway regulator; preferably, the immune signaling pathway regulator is one or more reagents selected from PD-1/PDL-1, PD-1/PDL-2, CD28/B7-1 (CD80), CD28/B7-2 (CD86), CTLA4/B7-1 (CD80), CILA4/B7-2 (CD86), 4-1BB (CD137)/4-1BBL (CD137L), ICOS/B7RP1, CD40/CD40L, Herpesvirus entry mediator (HVEM)/B- and T-lymphocyte attenuator (BTLA), OX40/OX40L, CD27/CD70, GITR/GITRL, KIR/MHC, lymphocyte activation gene 3 (LAG3 or CD223)/MHC, mucin domain of TIM3/TIM3 ligand, T cell immune receptor with Ig and ITIM domains (TIGIT)/CD96, TIGIT/CD226; and more preferably, the immune signaling pathway regulator is a PD-1 inhibitor, preferably a PD-1 antibody. 
     
     
         5 . The method according to  claim 1 , wherein the tumor is a digestive tract tumor or breast tumor, preferably a colorectal cancer or breast cancer. 
     
     
         6 . The method according to  claim 1 , wherein the method is used for tumor immunotherapy; preferably, the method can improve a therapy response of a patient to the PD-1 inhibitor; more preferably, the method can prolong patient's survival time, inhibit tumor growth, and/or improve enrichment of anti-tumor immune cells at a tumor site; and preferably, the anti-tumor immune cells are selected from one or more of CD4+CD62L-CD44+, CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+, and/or Gr-1+CD86+. 
     
     
         7 . The method according to  claim 1 , wherein the method can simultaneously improve the therapy response of patient to the PD-1 inhibitor, prolong patient's survival time, inhibit tumor growth, and improve enrichment of anti-tumor immune cells at the tumor site; the anti-tumor immune cells comprise CD4+CD62L-CD44+, CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+ and Gr-1+CD86+; and the method can improve enrichment of anti-tumor immune cells CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+ and Gr-1+CD86+ at the tumor site compared with treatment with the immune signaling pathway regulators alone. 
     
     
         8 . The method according to  claim 1 , wherein a single dosage of the probiotic is at least 1-20×10 9  CFU, or at least 2-18×10 9  CFU, or at least 3-15×10 9  CFU, or at least 4-12×10 9  CFU, or at least 5-6×10 9  CFU; and preferably, the single dosage of the probiotic is at least 5-10×10 9  CFU. 
     
     
         9 . The method according to  claim 1 , wherein the probiotic is an oral preparation, preferably one or more of lyophilized powder, tablets, capsules, solution, and suspension. 
     
     
         10 . The method according to  claim 4 , wherein the probiotic and the other tumor treatment drug are used or not used at the same time. 
     
     
         11 . A pharmaceutical composition for tumor treatment, comprising a probiotic and a pharmaceutically acceptable carrier, wherein the probiotic comprises  Bifidobacterium animalis  subsp.  lactis.    
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein the probiotic comprises  Bifidobacterium animalis  subsp.  lactis  NexStrain 02 (Accession Number: CGMCC No. 20455). 
     
     
         13 . The pharmaceutical composition according to  claim 11 , wherein the probiotic comprises a bacterium with an evolutionary distance of less than 0.005 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;
 preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.001 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;   preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.0005 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;   preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.00005 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;   preferably, the probiotic comprises a bacterium with an evolutionary distance of 0 from the  Bifidobacterium animalis  subsp.  lactis  NexStrain 02;   wherein the maximal unique match (MUM) between two genomes is calculated from the evolutionary distance by using a suffix tree algorithm of parsnp software, MUMi is calculated by using MUM, and a value of the MUMi is a distance between the two genomes; and a MUMi calculation method is:
   MUMi=1 −L mum/ L av, 
   wherein the Lmum refers to a base number of all MUMs, and Lav refers to a mean of the base numbers of the two genomes.   
     
     
         14 . The pharmaceutical composition according to  claim 11 , wherein the tumor treatment further comprising an application of one or more other tumor therapeutic drugs; preferably, the tumor therapeutic drug is an immune signaling pathway regulator; preferably, the immune signaling pathway regulator is one or more reagents selected from PD-1/PDL-1, PD-1/PDL-2, CD28/B7-1 (CD80), CD28/B7-2 (CD86), CTLA4/B7-1 (CD80), CILA4/B7-2 (CD86), 4-1BB (CD137)/4-1BBL (CD137L), ICOS/B7RP1, CD40/CD40L, Herpesvirus entry mediator (HVEM)/B- and T-lymphocyte attenuator (BTLA), OX40/OX40L, CD27/CD70, GITR/GITRL, KIR/MHC, lymphocyte activation gene 3 (LAG3 or CD223)/MHC, mucin domain of TIM3/TIM3 ligand, T cell immune receptor with Ig and ITIM domains (TIGIT)/CD96, TIGIT/CD226; and more preferably, the immune signaling pathway regulator is a PD-1 inhibitor, preferably a PD-1 antibody. 
     
     
         15 . The pharmaceutical composition according to  claim 11 , wherein the tumor is a digestive tract tumor or breast tumor, preferably a colorectal cancer or breast cancer. 
     
     
         16 . The pharmaceutical composition according to  claim 11 , wherein the pharmaceutical composition is used for tumor immunotherapy; preferably, the pharmaceutical composition can improve a therapy response of a patient to the PD-1 inhibitor; more preferably, the pharmaceutical composition can prolong patient's survival time, inhibit tumor growth, and/or improve enrichment of anti-tumor immune cells at a tumor site; and preferably, the anti-tumor immune cells are selected from one or more of CD4+CD62L-CD44+, CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+, and/or Gr-1+CD86+. 
     
     
         17 . The pharmaceutical composition according to  claim 11 , wherein the pharmaceutical composition can simultaneously improve the therapy response of patient to the PD-1 inhibitor, prolong patient's survival time, inhibit tumor growth, and improve enrichment of anti-tumor immune cells at the tumor site; the anti-tumor immune cells comprise CD4+CD62L-CD44+, CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+ and Gr-1+CD86+; and the pharmaceutical composition can improve enrichment of anti-tumor immune cells CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+ and Gr-1+CD86+ at the tumor site compared with treatment with the immune signaling pathway regulators alone. 
     
     
         18 . The pharmaceutical composition according to  claim 11 , wherein a single dosage of the probiotic is at least 1-20×10 9  CFU, or at least 2-18×10 9  CFU, or at least 3-15×10 9  CFU, or at least 4-12×10 9  CFU, or at least 5-6×10 9  CFU; and preferably, the single dosage of the probiotic is at least 5-10×10 9  CFU. 
     
     
         19 . The pharmaceutical composition according to  claim 11 , wherein the pharmaceutical composition is an oral preparation, preferably one or more of lyophilized powder, tablets, capsules, solution, and suspension. 
     
     
         20 . The pharmaceutical composition according to  claim 14 , wherein the probiotic and the other tumor therapeutic drugs are used or not used at the same time.